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Discovery of PVD-06 as a Subtype-Selective and Efficient PTPN2 Degrader

文献类型：期刊论文

作者Hu, Linghao2,3; Li, Huiyun2,4; Qin, Junlin5,6; Yang, Dan2,7; Liu, Jieming2; Luo, Xiaomin2; Ma, Jingkun8; Luo, Cheng1,2,5,6; Ye, Fei9; Zhou, Yubo2,8
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2023-11-15
卷号66期号:22页码:15269-15287
ISSN号0022-2623
DOI10.1021/acs.jmedchem.3c01348
通讯作者Ye, Fei(yefei@zstu.edu.cn) ; Zhou, Yubo(ybzhou@simm.ac.cn) ; Li, Jia(jli@simm.ac.cn) ; Wang, Mingliang(wangmingliang@simm.ac.cn)
英文摘要Protein tyrosine phosphatase nonreceptor Type 2 (PTPN2) is an attractive target for cancer immunotherapy. PTPN2 and another subtype of PTP1B are highly similar in structure, but their biological functions are distinct. Therefore, subtype-selective targeting of PTPN2 remains a challenge for researchers. Herein, the development of small molecular PTPN2 degraders based on a thiadiazolidinone dioxide-naphthalene scaffold and a VHL E3 ligase ligand is described, and the PTPN2/PTP1B subtype-selective degradation is achieved for the first time. The linker structure modifications led to the discovery of the subtype-selective PTPN2 degrader PVD-06 (PTPN2/PTP1B selective index > 60-fold), which also exhibits excellent proteome-wide degradation selectivity. PVD-06 induces PTPN2 degradation in a ubiquitination- and proteasome-dependent manner. It efficiently promotes T cell activation and amplifies IFN-gamma-mediated B16F10 cell growth inhibition. This study provides a convenient chemical knockdown tool for PTPN2-related research and a paradigm for subtype-selective PTP degradation through nonspecific substrate-mimicking ligands, demonstrating the therapeutic potential of PTPN2 subtype-selective degradation.
WOS关键词PROTEIN-TYROSINE-PHOSPHATASE ; CRYSTAL-STRUCTURE ; STRUCTURAL BASIS ; DEGRADATION ; PTP1B ; 1B ; INHIBITION ; FEATURES ; LIBRARY
资助项目China Postdoctoral Science Foundation[2019B090904008] ; Guangdong High-level New RD Institute[2021B0909050003] ; Guangdong High-level Innovative Research Institute[22YF1457600] ; Shanghai Science and Technology Development Funds[2021M703348] ; China Postdoctoral Science Foundation[82273951] ; China Postdoctoral Science Foundation[82121005] ; National Natural Science Foundation of China
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者AMER CHEMICAL SOC
WOS记录号WOS:001141293200001
源URL[http://119.78.100.183/handle/2S10ELR8/308654]  
专题中国科学院上海药物研究所
通讯作者Ye, Fei; Zhou, Yubo; Li, Jia; Wang, Mingliang
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Chem Biol, Shanghai 201203, Peoples R China
2.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Guangdong, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China
4.Zunyi Med Univ, Sch Pharm, Zunyi 563000, Guizhou, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China
6.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
7.Southern Med Univ, Sch Pharmaceut Sci, Guangzhou 510515, Guangdong, Peoples R China
8.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China
9.Zhejiang Sci Tech Univ, Coll Life Sci & Med, Hangzhou 310018, Peoples R China
推荐引用方式
GB/T 7714		 Hu, Linghao,Li, Huiyun,Qin, Junlin,et al. Discovery of PVD-06 as a Subtype-Selective and Efficient PTPN2 Degrader[J]. JOURNAL OF MEDICINAL CHEMISTRY,2023,66(22):15269-15287.
APA Hu, Linghao.,Li, Huiyun.,Qin, Junlin.,Yang, Dan.,Liu, Jieming.,...&Wang, Mingliang.(2023).Discovery of PVD-06 as a Subtype-Selective and Efficient PTPN2 Degrader.JOURNAL OF MEDICINAL CHEMISTRY,66(22),15269-15287.
MLA Hu, Linghao,et al."Discovery of PVD-06 as a Subtype-Selective and Efficient PTPN2 Degrader".JOURNAL OF MEDICINAL CHEMISTRY 66.22(2023):15269-15287.

入库方式： OAI收割

来源：上海药物研究所

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